Natural killer T cells (NKT cells) are selected in the thymus by self-glycolipid antigens presented by CD1d molecules. It is currently thought that one specific component of the lysosomal processing pathway, which leads to the production of isoglobotrihexosylceramide (iGb3), is essential for normal NKT cell development. New evidence now shows that NKT cell development can be disrupted by a dive...

A polymeric nanogel has been used to sequester and turn off a lysosomal protein, acid α-glucosidase (GAA). The nanogel contains a β-thiopropionate cross-linker, which endows the nanogel with pH-sensitivity. While encapsulation of the enzyme fully turns off its activity, approximately 75% of the activity is recovered upon reducing the pH to 5.0. The recovered activity is ascribed to pH-induced d...

Induced pluripotent stem cells (iPSCs) have provided new opportunities to explore the cell biology and pathophysiology of human diseases, and the lysosomal storage disorder research community has been quick to adopt this technology. Patient-derived iPSC models have been generated for a number of lysosomal storage disorders, including Gaucher disease, Pompe disease, Fabry disease, metachromatic ...

Gaucher disease (GD), the most common lysosomal storage disease, is caused by mutations in GBA1 encoding of β-glucocerebrosidase (GCase). Recently it was reported that progranulin (PGRN) insufficiency and deficiency associated with GD in human and mice, respectively. However the underlying mechanisms remain unknown. Here we report that PGRN binds directly to GCase and its deficiency results in ...

Mutations in proteins that induce misfolding and proteasomal degradation are common causes of inherited diseases. Fabry disease is a lysosomal storage disorder caused by a deficiency of alpha-galactosidase A activity in lysosomes resulting in an accumulation of glycosphingolipid globotriosylceramide (Gb3). Some classical Fabry hemizygotes and all cardiac variants have residual alpha-galactosida...

Loss of the lysosomal ClC-7/Ostm1 2Cl /H exchanger causes lysosomal storage disease and osteopetrosis in humans and additionally changes fur colour in mice. Its conversion into a Cl conductance in Clcn7 mice entails similarly severe lysosomal storage, but less severe osteopetrosis and no change in fur colour. To elucidate the basis for these phenotypical differences, we generated Clcn7 mice exp...

Analysis of lipid storage in postmortem brains of patients with amaurotic idiocy led to the recognition of five lysosomal ganglioside storage diseases and identification of their inherited metabolic blocks. Purification of lysosomal acid sphingomyelinase and ceramidase and analysis of their gene structures were the prerequisites for the clarification of Niemann-Pick and Farber disease. For lipi...

Morquio A syndrome is a lysosomal storage disease associated with mucopolysaccharidosis. It is caused by a deficiency of the lysosomal enzyme, N-acetylgalactosamine-6-sulfate sulfatase, which leads to accumulation of keratan sulfate and condroitin-6 sulfate in multiple organs. Patients present with multisystemic complications involving the musculoskeletal, respiratory, cardiovascular, and diges...

The mucopolysaccharidoses (MPSs) are lysosomal storage diseases resulting from impaired catabolism of sulfated glycosaminoglycans. MPS VII mice lack lysosomal beta-glucuronidase (GUSB) activity, leading to the accumulation of partially degraded chondroitin, dermatan, and heparan sulfates in most tissues. Consequently, these mice develop most of the symptoms exhibited by human MPS VII patients, ...

Saposin deficiency is a childhood neurodegenerative lysosomal storage disorder (LSD) that can cause premature death within three months of life. Saposins are activator proteins that promote the function of lysosomal hydrolases that mediate the degradation of sphingolipids. There are four saposin proteins in humans, which are encoded by the prosaposin gene. Mutations causing an absence or impair...